Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug

Abstract

We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.

Conflict of interest statement

Declaration of Interest Statement:

Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1:. Pharmacokinetic (Cmax)/Pharmacodynamic (First-in-Morning Cortisol Level) Analysis after 14 Days of Daily Vamorolone Therapy.

Blood samples were drawn in the morning pre-dose after 2 weeks of daily vamorolone therapy. Each dot represents an individual patient. Adrenal suppression is defined as a first-morning cortisol of

Figure 2:. Line graphs of exploratory safety biomarkers demonstrating absolute change in Relative Fluorescence Units (RFU) from Baseline to Day 14 in VBP15–002.

Shown are 4 dose levels. Baseline values were compared with Day 14 values using a two-tailed paired t-test. Asterisks (*) indicate significant increases from baseline (pre-dose) to following 2 weeks of treatment (post-dose) for a given dose level (pAbbreviations: BL= baseline; RFU = Relative Fluorescence Units; MMP3 = matrix metalloproteinase 3; IGFBP5 = insulin-like growth factor binding protein-5.

Figure 3:

Line graphs of exploratory efficacy biomarkers demonstrating absolute change in Relative Fluorescence Units (RFU) from Baseline to Day 14 in VBP15–002. Shown are 4 dose levels. Baseline values were compared with Day 14 values using a two-tailed paired t-test. Asterisks (*) indicate significant increases from baseline (pre-dose) to following 2 weeks of treatment (post-dose) for a given dose level (pAbbreviations: BL= baseline; RFU = Relative Fluorescence Units; MDC = macrophage-derived chemokine; IL22 BP = interleukin-22 binding protein; IGFBP2 = insulin-like growth factor binding protein 2; ITGA1 ITGB1 = integrin a1b1; MMP 12 = matrix metalloproteinase 12

Figure 4:

Change in CK activity from baseline to 2 weeks of daily vamorolone treatment, and from baseline to 4 weeks (following 2 weeks of daily vamorolone dosing, and 2 weeks washout) in VBP15–002. Shown is the mean percent change ± standard deviation. Baseline values were compared using a two-tailed paired t-test; there was no adjustment for multiple comparisons. Asterisks (*) indicate significant p-value Abbreviations: CK = creatine kinase.